Domingos Dias Diogo Médico Cardiologista HCM Anticoagulcão Oral Domingos Dias Diogo Médico Cardiologista HCM

Anticoagulacão Oral / Fibrilhacão Atrial Responsável por cerca de 10% de mortes no mundo. 6 milhões de óbitos por ano. Atinge as classes sociais mas desfavorecidas .

Anticoagulacão Oral / Fibrilhacão Atrial Causa morte prematura Incapacita pessoas na faixa etária produtiva 70% não torna ao trabalho 50% tornam se dependentes de terceiros

Anticoagulacão Oral / Fibrilhacão Atrial Antagonistas de vitamina K reduzem: 62% do risco de AVC em pacientes em FA So 25 a 50% fazem uso da anticoagulacão ??? Factores Economicos/financeiros Dificuldades da monitorizacão Preocupacão com as complicacões hemorragicas.

Anticoagulacão Oral Tromboembolismo com indicacão a anticoagulacão: Fibrilhacão atrial / Flutter Atrial Proteses Mecanicas(cardiacas) Proteses Biologicas Doenca Reumatica Valvular TEV e arterial Cirurgias cardicas/HParterial Trombos em cavidades cardiacas e EAM.

Propriedades de um anticoagulante ideal Properties of rivaroxaban Propriedades de um anticoagulante ideal

Quais sao as propriedades de um anticoagulante ideal? Properties of rivaroxaban Administração Oral Conveniente para uso hospitalar ou ambulatório Janela terapêutica larga Margem de segurança mais ampla para uma grande variabilidade da dose efectiva Baixo risco de interacção com outras drogas ou alimentos Uso facilitado independentemente da dieta ou de outras terapêuticas Previsibilidade Segurança e eficácia na anti coagulação desde a primeira dose. Não necessidade de monitorização Sem necessidade de monitorização da coagulação –poupança de gastos Dose Fixa Doses fixas para a maioria dos doentes ausência da necessidade de ajustamentos de dose. This slide sets out some of the key properties of an ideal anticoagulant.

Propriedades de um anticoagulante ideal versus Agentes disponíveis actualmente Properties of rivaroxaban Oral No significant food/drug interactions Predictable response No routine coagulation monitoring Fixed dosing No HIT IDEAL  LMWH UFH Fondaparinux Warfarin None of the currently available anticoagulant agents meet the criteria of an ideal anticoagulant. Low-molecular-weight heparins (LMWHs) require injection and carry the risk of heparin-induced thrombocytopenia (HIT). Heparin has the same limitations as LMWHs but also requires frequent dose adjustments and coagulation monitoring. Fondaparinux requires injection and has a slow offset of action. Warfarin requires frequent monitoring and dose adjustments, and interacts with numerous foods and drugs. HIT, heparin-induced thrombocytopenia.

O Racional para a Inibição do Factor Xa. Properties of rivaroxaban O Racional para a Inibição do Factor Xa.

The coagulation pathway Properties of rivaroxaban TF VIIa Initiation X IX Propagation Xa IXa II Prothrombin Inactive factor This slide shows a simplified model of the coagulation pathway. Factor Xa plays a central role in the coagulation pathway. One molecule of Factor Xa catalyses the formation of approximately 1000 molecules of thrombin. Reference Turpie AGG. Arterioscler Thromb Vasc Biol 2007;27:123847. Active factor Transformation IIa Catalysis Thrombin Clot formation Fibrinogen Fibrin

Anticoagulants in development have single targets Properties of rivaroxaban Initiation TF VIIa Indirect Fondaparinux Idraparinux biotinylated X IX AT Xa IXa Propagation Prothrombin II Direct Rivaroxaban Apixaban Edoxaban Betrixaban YM-150 Direct Lepirudin Bivalirudin Argatroban Dabigatran TGN-167 Inactive factor This slide shows a simplified model of the coagulation pathway. Anticoagulants can be broadly categorized as: interfering with the initiation of coagulation (tissue factor [TF]–Factor VIIa complex inhibitors) interfering with the propagation of coagulation (indirect via antithrombin [AT] and direct inhibitors of Factor Xa or IXa) inhibiting thrombin activity. The TF–VIIa complex is key to the initiation of coagulation and is therefore potentially an important target. Inhibitors of TF–VIIa (such as nematode anticoagulant proteins, TF-pathway inhibitors and small molecules that inhibit the active site of Factor VIIa) are in the early stages of development. However, inhibitors of TF–VIIa would primarily affect the extrinsic rather than the intrinsic coagulation pathway. Factor Xa and thrombin are the only components of the coagulation cascade common to both the extrinsic and intrinsic coagulation pathways. Factor Xa and thrombin are attractive targets for therapeutic interventions. Reference Spyropoulos AC. Expert Opin Investig Drugs 2007;16:431–40. Active factor Transformation IIa Thrombin Catalysis Clot formation Fibrinogen Fibrin Adapted from Spyropoulos AC. Expert Opin Investig Drugs 2007;16:431–40. AT, antithrombin

A Trombina tem muitas funções alem de ser um procoagulante Properties of rivaroxaban Procoagulant Fibrin clot and platelet plug Feedback activation of coagulation Clot stabilization Anticoagulant Protein C activation Prostacyclin formation As várias funções da Trombina Inflammation P-selection expression Neutrophil–monocyte adhesion Chemotactic for PMNs Endothelial PAF formation Thrombin has many functions within and outside of the coagulation pathway, including acting as an anticoagulant. The only known functions of Factor Xa are to promote coagulation and inflammation; therefore, disruption of Factor Xa is less likely to have pleiotropic effects. Reference Turpie AGG. Arterioscler Thromb Vasc Biol 2007;27:1238–47. Cellular proliferation Direct mitogen for fibroblasts PDGF and TGF-β from platelets PDGF formation in endothelium PAF, platelet-activating factor; PDGF, platelet-derived growth factor; PMN, polymorphonuclear leukocyte; TGF, transforming growth factor. Esmon CT. Thromb Haemost 2009.

Rivaroxaban: modo de acção Properties of rivaroxaban Rivaroxaban: modo de acção

Rivaroxaban: O primeiro inibidor oral directo do factor Xa Properties of rivaroxaban Inibidor directo, especifico e competitivo do Factor Xa Inhibe a actividade do Factor Xa livre ou ligado a fibrina e a actividade da prothrombinase Inhibe o aparecimento da trombina Não tem efeito directo na agregação plaquetária induzida pela trombina e portante na homeostase primaria. Rivaroxaban (formerly BAY-59-3979) directly binds to human Factor Xa, as demonstrated in this slide of the X-ray crystal structure of rivaroxaban in complex with human Factor Xa. Supported by two hydrogen bonds, the (S)-oxazolidinone core of rivaroxaban provides the L-shape needed for binding to Factor Xa. It serves as a central template for directing the substituents into the S1 and S4 subsites. Binding is specific and competitive. References Roehrig S et al. J Med Chem 2005;48:5900–8. Perzborn E et al. J Thromb Haemost 2005;3:514–21. Roehrig S et al. J Med Chem 2005;48:5900–8; Perzborn E et al. J Thromb Haemost 2005;3:514–21.

Properties of rivaroxaban Rivaroxaban: Dose

Rivaroxaban 10 mg label statement: age, weight and gender Properties of rivaroxaban Patients above 65 years No dose adjustment Body weight Gender Children and adolescents Not recommended for use in children or adolescents below 18 years of age due to a lack of data on safety and efficacy This slide summarizes the use of rivaroxaban 10 mg in adult patients depending on their characteristics. Patients above 65 years No dose adjustment. Gender Body weight Children and adolescents Not recommended for use in children or adolescents below 18 years of age due to a lack of data on safety and efficacy. Reference Summary of Product Characteristics. http://www.emea.europa.eu/humandocs/PDFs/EPAR/xarelto/H-944-PI-en.pdf. Last accessed: 25/09/09. Summary of Product Characteristics. http://www.emea.europa.eu/humandocs/PDFs/EPAR/xarelto/H-944-PI-en.pdf Last accessed: 25/09/09.

Properties of rivaroxaban Conclusões

Clinical utility of rivaroxaban 10 mg Properties of rivaroxaban In patients undergoing elective hip or knee replacement surgery One tablet, once daily Does not require injection or routine coagulation monitoring Potent and rapid anticoagulant effects (within 2–4 hours) High oral bioavailability: > 80% Low potential for drug–drug or food–drug interactions* Fixed dose in adult patients regardless of age, gender and extreme body weight *For full details please see the rivaroxaban summary of product characteristics. Summary of Product Characteristics. http://www.emea.europa.eu/humandocs/PDFs/EPAR/xarelto/H-944-PI-en.pdf Last accessed: 25/09/09.

Study Design Atrial Fibrillation Rivaroxaban Warfarin G02-536 w_script.ppt Study Design Properties of rivaroxaban 3/23/2017 7:03:59 PM Risk Factors CHF Hypertension Age  75 Diabetes OR Stroke, TIA or Systemic embolus At least 2 or 3 required* Atrial Fibrillation Rivaroxaban Randomize Double Blind / Double Dummy (n ~ 14,000) Warfarin 20 mg daily 15 mg for Cr Cl 30-49 ml/min INR target - 2.5 (2.0-3.0 inclusive) Monthly Monitoring Adherence to standard of care guidelines Primary Endpoint: Stroke or non-CNS Systemic Embolism * Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10% 18

Primary Efficacy Outcome Stroke and non-CNS Embolism Properties of rivaroxaban Primary Efficacy Outcome Stroke and non-CNS Embolism Rivaroxaban Warfarin Event Rate 1.71 2.16 Warfarin Rivaroxaban Cumulative event rate (%) HR (95% CI): 0.79 (0.66, 0.96) P-value Non-Inferiority: <0.001 Days from Randomization No. at risk: Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634 Warfarin 7004 6327 5911 5542 4461 3478 2539 1538 655 Event Rates are per 100 patient-years Based on Protocol Compliant on Treatment Population

Primary Efficacy Outcome Stroke and non-CNS Embolism Properties of rivaroxaban Primary Efficacy Outcome Stroke and non-CNS Embolism   Rivaroxaban Warfarin Event Rate HR (95% CI) P-value On Treatment N= 14,143 1.70 2.15 0.79 (0.65,0.95) 0.015 ITT N= 14,171 2.12 2.42 0.88 (0.74,1.03) 0.117 Rivaroxaban better Warfarin better Event Rates are per 100 patient-years Based on Safety on Treatment or Intention-to-Treat thru Site Notification populations

Prevenção de AVC e Embolismo na Fibrilhação Auricular Rivaroxabano Reduz Significativamente o Risco de AVC em Doentes com Fibrilhação Auricular, com Segurança Comparável à da Varfarina, num Estudo Pivô de Fase III. O estudo ROCKET AF demonstrou a superioridade do rivaroxabano, em toma única diária, comparativamente à varfarina, na protecção do AVC e embolismo sistémico fora do SNC em doentes com fibrilhação auricular.

Prevenção de AVC e Embolismo na Fibrilhação Auricular Rivaroxabano demonstrou níveis comparáveis de taxas de hemorragia major e não major clinicamente relevantes semelhantes às da varfarina, bem como taxas de hemorragia intracraniana significativamente mais baixas do que as associadas à varfarina. ROCKET AF é o sétimo estudo clínico de Fase III com rivaroxabano a demonstrar melhoria consistente dos resultados, comparativamente às terapêuticas padrão.

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